Intranasal passive vaccines: thinking beyond the jab
Thoughts on Lumen’s new collaboration to fight flu with inhaled antibodies
By Jake Siegel and Brian Finrow
Last week we announced a new collaboration with Aridis Pharmaceuticals to develop an intranasal passive vaccine to fight flu. We have written before about our efforts to use our unique manufacturing platform to develop edible antibody drugs for a wide range of infectious diseases. Now, we’re excited to explore a different delivery method for our biologic drugs: through the nose and upper airways.
The news comes not long after most of us in the northern hemisphere rolled up our sleeves for the annual flu shot. This offers a good opportunity to ‘think beyond the jab’ when it comes to vaccines.
Nearly all vaccines are given as injections into muscle, but nearly all viral and bacterial villains attack us through the mucosal tissues of the mouth, nose, GI tract, and respiratory tract. Most vaccines available today are also what are known as active vaccines, which teach your body to make antibodies against germs.
By contrast, passive vaccines deploy lab-made antibodies or other protective proteins at those susceptible surfaces, offering an immediate response to invaders, a good example being Regeneron’s two-antibody cocktail for Covid-19. The “passive” here indicates that your immune system doesn’t have to get involved — an important feature for the millions who lack a fully functioning immune system!
Lumen’s strategy combines both innovations: making a passive vaccine and delivering it directly to the upper respiratory tract tissues at highest risk rather than by injection or I.V. The strategy is intuitive: banks beef up security where the bad guys are most likely to break in; safe and effective passive immunotherapies could let medicine do the same.
At least that’s the long-dreamed of theory. It’s a simple, powerful idea, but with a few rare exceptions the biotechnology industry has struggled to make passive vaccines a reality. High manufacturing and development costs have made it impractical to deliver daily doses of protein therapeutics at mass scale.
Lumen’s more scalable drug-making platform opens the door to finally realizing this elegant idea’s full potential.
Breathe easy: safely delivering VHHs to the upper respiratory tract
The first key question the Gates-funded work will answer is whether such spirulina-produced biologic drugs are safe and well-tolerated when inhaled.
Fortunately a lot is already known. To begin with we know that even whole spirulina biomass is well tolerated by mice when administered intranasally (we will have a paper out on this soon). And researchers have spent years studying how to safely deliver antibodies and other drugs deep into the lungs.
But we’re taking a different — and inherently safer — tack: targeted delivery just to the upper respiratory tract (URT). This is safe, easy, and well-established. Further, the URT is an environment that is quite amenable to foreign stuff. (Raise your hand if you’ve wiped away brown boogers after a mask-free session with a circular saw working on a home-improvement project.) In fact, the bodily tissues there are similar in many ways to the inner lining of the gastrointestinal tract, where Lumen has already generated clinical data showing spirulina-delivered therapeutic proteins are safe and well-tolerated. Both are bombarded daily with vast amounts of viruses, bacteria, fungi, strange proteins, and other foreign material. And both harbor a dense and helpful group of commensal organisms that are tolerated by our immune systems.
It therefore shouldn’t surprise anyone that the regulations and guidance documents promulgated by the FDA and other regulatory bodies do not mandate sterility for intra-nasally administered drugs.[1] In fact, they don’t even require purity; in the field of nasal probiotics the most popular supplier of lactobacillus appears to be the local dairy, and in the few papers that report any testing at all for adventitious organisms it is simple bioburden testing, akin to what’s required for food additives and nutritional supplements. Wild-type spirulina extract is one such FDA-regulated nutritional supplement, a fact that opened our minds to this interesting subfield. (These are minimum regulatory requirements, of course; our goal is always to far exceed the minimums where safety is concerned.)
So, while we won’t get ahead of the science, prior research points to a conclusion that antiviral VHH antibodies produced in spirulina can be safely inhaled.
mAbs and VHHs for the masses
As we’ve written elsewhere, producing antibodies and other therapeutic proteins in spirulina costs a fraction of other systems. That’s allowing us to take on prevalent diseases that existing technologies have failed to fully solve, including C. difficile, enterotoxigenic E. coli, cardiometabolic disease, and Covid-19.
Here, it enables a strategy for passive vaccines delivered directly to the site of flu infection. Interestingly, prior research indicates that the direct delivery of biologics to mucosal surfaces should actually require smaller dose size than systemic delivery — since the product stays concentrated where needed. (We are pleased to see that others are thinking along the same lines.)
Nevertheless, because more frequent dosing will be required — maybe even daily — we expect that the approach will require making far larger quantities of therapeutic proteins in the aggregate. Ultimately our goal is to enable daily administration to certain individuals during the period at risk, which might be during a hospital shift for a frontline healthcare worker or during the entire flu season for a vulnerable individual with a compromised immune system. This is a challenge for traditional antibody manufacturing approaches, which are already stretched thin due to the Covid-19 pandemic. But it is not a problem with Lumen’s platform, which cranks out vastly larger volumes of therapeutic protein for orders of magnitude less than existing technologies.
The final form of those cheaply produced proteins is a shelf-stable powder. So we can easily ship this product anywhere in the world without the cost and logistical complexity of a cold chain — another set of challenges that has bedeviled attempts to make monoclonal antibodies widely available for influenza, Covid-19, and other respiratory pathogens. Conveniently, this approach could also provide some relief for the non-trivial problem of needle fear, which may affect up to a quarter of adults and leads many to drag their feet to the vaccination site.
Passive immunization against more pathogens
This collaboration targets influenza, but the foundational work could easily extend to other respiratory viruses. And right now, none looms larger than SARS-CoV-2. Even with Covid vaccines now delivered into several billion arms, there is still an urgent need for alternatives, particularly during surges like Omicron. Eliminating the need for syringes, trained healthcare professionals, and cold-chain storage could help accelerate delivery of treatments in remote and unindustrialized regions. Further, immunocompromised subjects like infants, the elderly, and cancer patients are at the highest risk but least likely to respond to active vaccines.
Several research teams have published encouraging preclinical results that block SARS-CoV-2 transmission through intranasal and inhaled delivery of single-domain nanobodies, aka neutralizing VHHs, and other therapeutic proteins. And fortunately we’ve already got a head start on that from our ongoing DoD-funded Covid-19 program targeting the gastrointestinal manifestations of the disease.
But for now, we will keep our sights on influenza. And who knows? Perhaps the annual poke will become a thing of the past…
Jake Siegel is a scientific writer at Lumen Bioscience; Brian Finrow is Lumen’s cofounder and CEO.
[1] For those of us trained in the context of traditional injected antibody drug development this does, in fact, tend to be very surprising.
